1. Randomized phase III trial of trabectedin versus doxorubicin-based chemotherapy as first-line therapy in translocation-related sarcomas (TRS)
Sant P. Chawla, Andrew Hendifar, Michael Leahy, Antoine Italiano, Shreyaskumar Patel, Peter Hohenberger, Armando Santoro, Arthur P. Staddon, Nicolas Penel, Sophie Piperno-Neumann, Pilar Lardelli, Antonio Nieto, Carmen Kahatt, Jean-Yves Blay
As the audience knows, trabectedin is a marine derived alkaloid that has demonstrated efficacy in soft tissue sarcoma.
This study was conducted to fulfill a specific obligation from the EMA: to identify predictors of response to trabectedin.
High response rate of trabectedin in myxoid liposarcomas is well-documented.
A trial was performed in order to verify if this higher activity extrapolated to other translocation related sarcomas as compared to doxorubicin containing regimens.

2. Study Design
An adaptive design in chemonaïve patients with advanced TRS, stratified by performance status and subtype, then randomized to receive:
Trabectedin: 1.5 mg/m2 in 24h iv infusion q3wk
Doxorubicin based chemotherapy (DXCT): single agent 75 mg/m2 q3wk, or 60 mg/m2 combined with ifosfamide 6-9 g/m2 q3wk
MRCL (n= 40)
Other TRS (n= 40)
RANDOMIZATION (1:1)
Eligible patients
PS= 0
PS= 1-2
An adaptive design was used as shown
80 chemonaïve patients were planned to be enrolled with at least 50% patients with myxoid liposarcoma.
Eligible patients were stratified by ECOG performance status and histological subtype (myxoid liposarcoma versus other histologies) and randomized 1:1 to receive trabectedin or doxorubicin based chemotherapy

3. Study Objectives
Primary: Progression free survival (PFS) of trabectedin vs DXCT
Secondary:
PFS at 6 months
Response rate (RR)
Overall survival
Safety
PFS/RR analyzed by investigator assessment for all randomized patients
PFS/RR analyzed by independent review only for confirmed TRS patients
Primary efficacy endpoint was progression-free survival.
After randomization, translocation was confirmed by FISH.
Secondary endpoints included progression-free survival at 6 months, response rates, overall survival and safety.
Response rates were analyzed for all randomized patients by investigator assessment and only TRS confirmed patients by independent review

4. Results: Baseline Characteristics
Trabectedin (n=61)
DXCT (n=60)
Age (yr)
Median (range)
47 (19-78)
49 (19-78)
Sex
Male / female
36 (59%) / 25 (41%)
38 (63%) / 22 (37%)
ECOG PS
28 (46%)
29 (48%) 1
32 (52%)
30 (50%) 2
1 (2%)
Sarcoma type by Investigator
MRCL
28 (47%)
Other
33 (54%)
32 (53%)
Sarcoma type by central pathology
23 (38%)
17 (28%)
20 (33%)
Not confirmed*
10 (16%)
A total of 121 patients were randomized , 61 to trabectedin arm and 60 to doxorubicin-based chemotherapy.
Baseline characteristics were well balanced as shown
Pathological review did not confirm TRS diagnosis and/or translocation in 33 of 121 randomized patients.
Therefore, TRS confirmed population consisted of 88 patients: 40 (33%) with MRCL and 48 (40%) with other TRS.
* Wrong diagnosis 4 (7%) and 9 (15%) patients of the trabectedin and DXCT arms, no evidence of translocation in 3 (5%) and 2 (3%) patients, and lack of available material for central review in 3 (5%) and 12 (20%) patients

5. Histology According Central Diagnosis (TRS Confirmed Patients N=88)
Trabectedin
(n=51)
DXCT
(n=37) N %
MYXOID LIPOSARCOMA 23
45.1 17
45.9
SYNOVIAL SARCOMA 15
29.4 9
24.3
ALVEOLAR SOFT PART SARCOMA 2
3.9
5.4
CLEAR CELL SARCOMA 3
5.9 4
10.8
DESMOPLASTIC SMALL ROUND CELL 1
2.0
2.7
EXTRASKELETAL MYXOID CHONDROSARCOMA 5
9.8
LOW GRADE ENDOMETRIAL STROMAL SARCOMA
LOW GRADE FIBROMYXOID SARCOMA .
As described earlier, almost 50% of patients in either arm had myxoid liposarcoma
Other histological sybtypes mainly included synovial sarcoma, alveolar soft part sarcoma, clear cell sarcoma and extraskeletal myxoid chondrosarcoma.
Ewings and Rhabdomyosarcoma were excluded due to high response rates seen with standard chemotherapy.

6. Results: Baseline Characteristics
Trabectedin (n=61)
DXCT (n=60)
Disease Extension
Locally advanced
18 (30%)
13 (22%)
Metastatic
43 (70%)
47 (78%)
Prior surgery (radical/palliative)
33 (54%)
38 (63%)
Prior radiotherapy
24 (39%)
21 (35%)
Number of sites involved at baseline, Median (range)
2 (1-8)
2 (1-5)
Months from first diagnosis to randomization, Median (range)
10 (1-187)
8 (0-310)
Patients with advanced or metastatic disease as well as patients receiving prior surgery and radiotherapy were also balanced as shown.

7. Patient Exposure
Trabectedin (n=61)
DXCT (n=57)
Number of cycles
441
264
Number of cycles per patient
Median (range)
5 (1-31)
6 (1-8)
Doxorubicin
single agent
(n=36)
plus ifosfamide
(n=21)
4 (1-8)
Time on treatment (weeks)
19.3 ( )
19.2 ( )
14.3 ( )
Median number of cycles was similar in both treatment arms but trabectedin could be administered indefinitely due to its lack of cumulative toxicities.

8. Censoring A high percentage of patients were censored in both arms
Main reasons for censoring:
Surgical removal of lesions
24% in trabectedin arm and 16% in the DXCT arm
Administration of a new anticancer therapy (chemotherapy or radiotherapy) before progression of the disease
18% in trabectedin arm and 24% in DXCT arm
Importantly, 35-40% patients in either arm ended up receiving the drug in the other arm
Patients in trabectedin arm also received DXCT
Patients in DXCT arm also received trabectedin
A high percentage of patients were censored in both treatment arms rendering the analyses underpowered. Censoring rate was balanced between both arms.
Main censoring reason was surgical lesion removal before disease progression
Other frequent censoring reason was administration of other anticancer therapy or radiotherapy before disease progression
Importantly, 35-40% patients in either arm received the opposite drug.
Patients in the trabectedin arm received doxorubicin based chemotherapy and vice-versa.

9. Results: Response Rate
Investigator Assessment
All randomized patients
Trabectedin (n=61)
DXCT (n=60)
Best objective response (RECIST) PR
5 (8%)
15 (25%)
0.0150 SD
40 (66%)
33 (55%)
DCR
45 (74%)
48 (80%) PD
11 (18%)
8 (13%) NE
4 (7%)
For all randomized patients, partial responses by RECIST were significantly higher in the doxorubicin based chemotherapy arm. But overall disease control rate was similar; 75% in both arms.

10. Results: Response Rate
Independent Review 
TRS confirmed patients
Trabectedin (n=51)
DXCT
(n=37)
p-value
Best objective response (RECIST) PR
3 (6%)
10 (27%)
0.0123 SD
39 (77%)
22 (60%)
DCR
42 (82%)
32 (87%) PD
6 (12%)
1 (3%) NE
4 (11%)
Histology of PR patients
2 MRCL
1 Synovial
5 MRCL
4 Synovial
1 Desmoplastic Round cell
For TRS confirmed patients, partial response rates were significantly higher for the doxorubicin based chemotherapy arm. However, disease control rate was again similar; 85% in both arms.
Response rates in the TRS confirmed patients were similar to the rates for all randomized patients.
In the Trabectedin arm, out of 3 patients who had partial response, 2 were Myxoid round cell liposarcomas and 1 was synovial sarcoma
In the doxorubicin based chemotherapy arm, out of 10 patients who had PR, 5 were again myxoid round cell LPS, 4 were synovial sarcomas and 1 was a desmoplastic round cell sarcoma

11. Results: PFS by Investigators
Median: 16.1 months (95% CI, )
Hazard ratio: 0.85, p= Log rank p=0.5533
Median: 8.8 months (95% CI, )
For all randomized patients, median PFS was 16 months in trabectedin arm versus 9 months in doxorubicin based chemotherapy arm, but given the high rate of censoring, was not statistically significant.

12. Results: PFS by Independent Review
Hazard ratio: 0.86; p= Stratified log-rank p=0.9573
Median: 18.8 months (95% CI, 5.7-not reached)
Median: 8.3 months (95% CI, )
For TRS confirmed patients, median PFS was 19 months in trabectedin arm versus 8 months in doxorubicin based chemotherapy arm, but again, given the high censoring, was not statistically significant.

13. Results: Overall Survival
Median: 27.3 months (95% CI, )
Median: 38.9 months (95% CI, 24.2-nr)
Hazard ratio: 0.77, p= Log rank p=0.3659
For all randomized patients, median overall survival was 39 months in trabectedin arm vs 27 months in doxorubicin- based chemotherapy arm, but was not statistically significant due to the high rate of censoring
Survival curves separated in favor of trabectedin after 20 months.

14. OS in Myxoid Liposarcoma
In subset analysis, which may not be kosher for the statistical aficionados in the audience, overall survival appears longer in patients with myxoid liposarcoma, but may not be valid due to the high censoring.
Median: 95% CI (-)
Median: % CI ( )
Hazard ratio: 0.25, p= Log rank p=0.0314

15. Results: Hematologic and Other Laboratory Toxicity
Trabectedin
DXCT
Grade1-2 (%)
Grade 3-4 (%)
Laboratory disorders
Neutropenia
25.0%
55.0%
10.7%
75%
Febrile neutropenia -
1.6%
12.3%
Thrombocytopenia
26.2%
16.4%
37.5%
14.3%
ALT increase
40.0%
53.3%
37.0%
1.9%
AST increase
51.7%
33.3%
ALKP increase
56.7%
5.0%
38.9%
Bilirubin increase
20.0%
1.7%
13.0%
CPK increase
34.5%
8.6%
8.2%
4.1%
Incidence of grade 3/4 neutropenia was higher in doxorubicin arm
The most common severe laboratory abnormality associated with trabectedin was transient transaminases elevation

16. Results: Non-Hematologic Toxicity
Trabectedin
DXCT
Grade1-2 (%)
Grade 3-4 (%)
Treatment related AEs
Fatigue
59.0%
6.5%
61.4%
1.8%
Nausea
68.9%
1.6%
64.9% -
Vomiting
42.6%
26.3%
Mucositis
4.9%
8.8%
Alopecia
43.9%
As expected, severe fatigue was seen more frequently in trabectedin arm while febrile neutropenia and mucositis were more commonly observed in doxorubicin-based chemotherapy arm.

17. Summary
The study was underpowered to detect any statistical significant differences in the two arms due to high rate of censoring in both arms
Overall, no statistically significant differences in PFS/OS were observed
Median PFS was 19 mo. in trabectedin arm vs. 8 mo. in DXCT arm
Median OS was 39 mo. in trabectedin arm vs. 27 mo. in DXCT arm
Safety profiles for trabectedin and DXCT were consistent with previous studies
Ability to administer trabectedin over prolonged periods without cumulative toxicity may allow for longer disease control
Trabectedin should be further explored in a definitive randomized study in myxoid liposarcoma patients
High rate of censoring in both arms rendered the study underpowered to detect any statistically significant differences.
No statistical significant differences were observed in PFS or OS.
As expected, safety profiles for both arms was consistent with previous studies
The ability to administer multiple cycles of trabectedin without significant cumulative toxicity may allow for longer disease control
Trabectedin deserves further exploration in a definitive randomized study in myxoid liposarcoma patients

18. Back-up slides

19. All randomized patients
Censoring Reasons
Efficacy population
Trabectedin (n=51)
DXCT (n=37)
Surgery
12 (24%)
6 (16%)
Chemotherapy
6 (12%)
7 (19%)
Radiotherapy
3 (6%)
2 (5%)
Last tumor assessmenta
5 (14%)
Otherb
2 (4%)
4 (11%)
Total
35 (69%)
24 (65%)
All randomized patients
Trabectedin (n=61)
DXCT(n=60)
11 (18%)
12 (20%)
5 (8%)
4 (7%)
3 (5%)
6 (10%)
9 (15%)
32 (52%)
34 (57%)
a Patients on follow-up for disease assessment or with event/subsequent therapy out of study window or without PD at last tumor assessment available in database at cut-off date.
b Censored at randomization (e.g.: untreated) or withdrawn due to related/unrelated adverse event or refusal before treatment onset/disease progression or new treatment out of study window.
Censoring rates were similar in both arms for both the primary efficacy population and the all randomized population. Surgical removal of the lesions was the most common reason for censure, and was similar in trabectedin and in Doxo-based chemotherapy arms.

20. Subsequent Chemotherapy Agents in Censored Patients
Trabectedin
(n=35)
DXCT
(n=24) N %
CEDIRANIB . 1
4.2
CYCLOPHOSPHAMIDE 2
5.7
8.3
DACARBAZINE
DOCETAXEL 3
8.6
DOXORUBICIN 10
28.6
12.5
DOXORUBICIN HYDROCHLORIDE
EPIRUBICIN
2.9
ETOPOSIDE
GEMCITABINE 5
14.3
IFOSFAMIDE 6
17.1 8
33.3
PAZOPANIB
SORAFENIB
SORAFENIB TOSILATE
SUNITINIB
TRABECTEDIN 4
11.4 9
37.5
VINORELBINE
VORINOSTAT
Chemotherapy agents given to patients with no disease progression, in both treatment arms. Patients were therefore censored for PFS.

21. Responders’ Histology
Patient
Treatment arm
Central Diagnosis
103013
Trabectedin
Synovial sarcoma
182003
Myxoid liposarcoma
21021
103008
DXCT
14034
Desmoplastic small round cell sarcoma
184025
191006
221011
33014
44016
71020
71026
72011
Histological subtype of sarcoma in patients who responded by RECIST (Independent Review).

22. Discontinuations and Dose Reductions
Trabectedin (n=61)
DXCT (n=57) n % N
Deaths associated with treatment- related AEs 1
1.6
1.8
Discontinuations associated with treatment-related AEs 10
16.4 6
10.5
Delays associated with treatment- related AEs 32
52.5 8
14.0
Dose reductions associated with treatment-related AEs 24
39.4
Administration delays and dose reductions occurred more frequently in the trabectedin arm, partially due to the prolonged treatment duration.
Transaminase increase was the main reason for dose reduction.
Neutropenia was the most common cause of administration delay. Neutropenia was controlled in trabectedin arm mainly with dose delay, while G-CSF was more frequently administered in Doxo arm (61.4% of patients) than in trabectedin arm (49.2%).
Administration delays and dose reductions occurred more frequently in the trabectedin arm, partially due to the prolonged treatment duration.
Transaminase increase was the main reason for dose reduction
Neutropenia was the most common cause of administration delay.

23. Results: Safety in DXCT
DXCT+Ifosfamide (n=21)
DXCT (n=36)
Grade1-2 (%)
Grade 3 (%)
Grade 4 (%)
Grade 4(%)
Treatment related AEs
Fatigue
57.1% -
63.9%
2.8%
Nausea
52.4%
72.2%
Vomiting
19.0%
30.6%
Mucositis
9.5%
4.8%
36.1%
11.1%
Alopecia
38.1%
47.2%
Febrile neutropenia
14.3%
5.6%
Laboratory disorders
Neutropenia
23.8%
42.9%
2.9%
34.3%
Thrombocytopenia
45.7%
5.7%
ALT increase
31.6%
5.3%
40.0%
AST increase
26.3%
Alkaline phosphatase increase
52.6%
31.4%
Bilirubin increase
10.5%
CPK increase
5.9%
12.5%
3.1%
Most frequent adverse events and laboratory abnormalities in patients from arm B (doxo-based chemotherapy), split by treatment type: doxorubicin alone or in combination with ifosfamide.